The risk of developing atherosclerosis, the leading cause of death in Western industrialized countries, is directly related to plasma concentrations of low density lipoprotein (LDL) cholesterol and inversely related to concentrations of high density lipoprotein (HDL) cholesterol (J. L. Breslow, in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; and S. M. Grundy, (1995) J. Am. Med. Assoc. 256: 2849).
The first observable event in the formation of an atherosclerotic plaque occurs when blood-borne monocytes adhere to the vascular endothelial layer and transmigrate through to the sub-endothelial space. In vitro data suggests that adjacent endothelial cells at the same time produce oxidized low density lipoprotein (LDL), which are taken up in large amounts by the monocytes through scavenger receptors expressed on their surfaces.
These lipid-filled monocytes are called foam cells, and are the major constituent of the fatty streak, which is characteristic of an atherosclerotic lesion. Interactions between foam cells and the endothelial and smooth muscle cells which surround them lead to a state of chronic local inflammation which can eventually lead to smooth muscle cell proliferation and migration, and the formation of a fibrous plaque. Such plaques occlude the blood vessel concerned and thus restrict the flow of blood, resulting in ischemia, a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion.
Although normal and pathologic LDL metabolism is well-defined (J. L. Goldstein, H. H. Hobbs, M. S. Brown in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 1981-2030), HDL metabolism is relatively poorly understood (J. L. Breslow, in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; S. M. Grundy, (1995) J Am. Med. Assoc. 256: 2849; G. Assman, A. von Eckardstein, H. B. Brewer Jr. in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2053-2072; W. J. Johnson et al., (1991) Biochim. Biophys. Acta 1085:273; M. N. Pieters et al., (1994) Ibid 1225:125; and C. J. Fielding and P. E. Fielding, (1995) J Lipid Res 36:211).
HDL delivers cholesteryl ester to nonplacental steroidogenic tissues (ovary, adrenal glands, and testis) for hormone synthesis (J. M. Anderson and J. M. Dietschy (1981) J. Biol. Chem. 256: 7362; M. S. Brown et al., (1979) Recent Prog Horm. Res. 35:215; J. T. Gwynne and J. F. Strauss III, (1982) Endocr. Rev. 3:299; B. D. Murphy et al., (1985) Endocrinology 116: 1587) and transports cholesterol from extrahepatic tissues to the liver (reverse cholesterol transport) e.g. for incorporation into bile (J. L. Breslow, in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; S. M. Grundy, (1995) J. Am. Med. Assoc. 256: 2849; G. Assman, A. von Eckardstein, H. B. Brewer Jr. in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2053-2072; W. J. Johnson et al., (1991) Biochim. Biophys. Acta 1085:273; M. N. Pieters et al., (1994) Ibid 1225:125; and C. J. Fielding and P. E. Fielding, (1995) J. Lipid Res 36.211).
Unlike LDL, wherein the protein component (apoB) is lysosomally degraded after endocytosis via the LDL receptor (J. L. Goldstein, H. H. Hobbs, M. S. Brown in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 1981-2030), HDL is delivered via "selective lipid uptake" in which the protein component (apoA) is not degraded (R. Wishart and M. MacKinnon (1990) Biochim. Biophys. Acta 1044:375).
The class B scavenger receptor, SR-BI, has been shown to bind HDL cholesterol and mediate uptake into tissue (Acton, S. et al., Science 271:518-520). In this lipid uptake pathway, HDL docks to SR-BI, delivers cholesterol esters and possibly other lipids to the cell, and then dissociates from SR-BI and resumes circulating in plasma. Excess LDL was not found to inhibit HDL association with SR-BI, suggesting that nLDL in vivo does not significantly interfere with HDL binding to SR-BI.
SR-BI has also been shown to bind with high affinity to modified proteins (e.g. acetylated LDL, oxidized LDL, maleylated bovine serum albumin) and native LDL (Acton, et al., (1994) J. Biochem 269:21003-21009). SR-BI and CD36, another class B scavenger receptor, have also been shown to bind anionic phospholipids, such as phosphatidylserine and phosphatidyl inositol, but not zwitterionic phospholipids, such as phosphatidylcholine, phosphatidylethanolamine and sphingomyelin. Competition studies suggest that anionic phospholipids bind to SR-BI at a site close to or identical with the sites of native and modified LDL binding and that the interaction may involve polyvalent binding via multiple anionic phospholipid molecules (Rigotti, A , S. Acton and M. Krieger (1995 J. Biochem 270:16221-16224).
SR-BI is expressed in a variety of cells and tissues including macrophages, endothelial cells, fat, lung, liver, adrenal gland and steroidogenic tissue.
Molecules involved upstream (e.g. activators or repressors) and/or downstream (whether positively or negatively regulated) of the SR-BI receptor in a lipid metabolic pathway would be useful in the prevention, treatment and diagnosis of diseases and conditions caused by abnormal or inappropriate lipid metabolism and/or transport, such as atherosclerosis and biliary tract disorders (e.g. gall stone formation).